Studies were initiated to unravel the function of surface variation of Neisseria gonorrhoeae and Neisseria meningitidis in the establishment of neisserial disease. Spontaneous variants and genetically defined recombinant strains differing in the expression of several major variable surface components - opacity outer membrane protein (Opa), Opc (meningococci only), lipopolysaccharide (LPS) and polysialic capsule (meningococci only), showed antigen variation-dependent binding to previously identified heparan sulfate containing mucosal cell-surface receptors. Adherence to these receptors is a first step towards Opa/Opc- dependent uptake of the bacteria by the mucosal cells. Confocal microscopy showed that this `invasion' into host cells was associated with a reorganization of the host cell actin cytoskeleton network and required phosphorylation of host cell tyrosine residues. Bacterial ligands for these receptors were identified for a number of clinical bacterial isolates. The functionality of the ligands (Opa/Opc), however, largely depended on the environmental conditions and the composition of the surface polysaccharides. Incorporation of sialic acids into the lipopolysaccharide hampered Opa protein function.